1. Field of the Invention
The invention relates to noninvasive sampling. More particularly, the invention relates to a sample probe interface method and apparatus for use in conjunction with an optically based noninvasive analyzer. More particularly, the invention relates to a dynamic probe interface, wherein at least part of a sample probe moves in a controlled fashion relative to a tissue sample to control spectral variations resulting from the sample probe displacement of the tissue sample during a sampling process.
2. Description of Related Art
Spectroscopy based noninvasive analyzers deliver external energy in the form of light to a specific sampling site, region, or volume of the human body where the photons interact with a tissue sample, thus probing chemical and physical features. A number of incident photons are specularly reflected, diffusely reflected, scattered, or transmitted out of the body where they are detected. Based upon knowledge of the incident photons and detected photons, the chemical and/or structural basis of the sampled site is deduced. A distinct advantage of a noninvasive analyzer is the analysis of chemical and structural constituents in the body without the generation of a biohazard in a pain-free manner with limited consumables. Additionally, noninvasive analyzers allow multiple analytes or structural features to be determined at one time. Examples herein focus on noninvasive glucose concentration estimation, but the principles apply to other noninvasive measurements of other blood or tissue analyte properties.
Diabetes
Diabetes is a chronic disease that results in abnormal production and use of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity play roles. Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics often have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide. Moreover, diabetes is merely one among a group of disorders of glucose metabolism that also includes impaired glucose tolerance and hyperinsulinemia, which is also known as hypoglycemia.
Sampling Methodology
A wide range of technologies serve to analyze the chemical make-up of the body. These techniques are broadly categorized into two groups, invasive and noninvasive. Herein, a technology that acquires any biosample from the body for analysis, beyond calibration, or if any part of the measuring apparatus penetrates through the outer layers of skin into the body, the technology is referred to as invasive. A number of noninvasive approaches for determining the glucose concentration in biosamples use spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-infrared (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)].
Noninvasive Glucose Concentration Estimation
There exist a number of noninvasive approaches for glucose concentration estimation or determination in tissue or blood. These approaches vary widely but have at least two common steps. First, an apparatus is used to acquire a photometric signal from the body. Second, an algorithm is used to convert this signal into a glucose concentration estimation.
One type of noninvasive glucose concentration analyzer is a system performing glucose concentration estimations from spectra. Typically, a noninvasive apparatus uses some form of spectroscopy to acquire a signal, such as a spectrum, from the body. A particular range useful for noninvasive glucose concentration estimation in diffuse reflectance mode is in the near-infrared from approximately 1100 to 2500 nm or one or more ranges therein, see K. Hazen, Glucose Determination in Biological Matrices Using Near-Infrared Spectroscopy, doctoral dissertation, University of Iowa (1995). These techniques are distinct from the traditional invasive and alternative invasive techniques in that the interrogated sample is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, one of several modes is used to collect noninvasive spectra including: transmittance, transflectance, and/or diffuse reflectance. In a transmittance-based concentration estimation, the signal collected, typically being light or a spectrum, is transmitted through a region of the body such as a fingertip. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point on the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region typically 0.2 to 5 mm or more away depending on the wavelength used.
Diffuse reflectance spectra are generally generated by capturing at least some of the photons exiting the skin surface with zero to a few millimeters of radial travel from the location that the incident photons penetrate into the skin. Typically, light that is strongly absorbed by the body such as light near water absorbance maxima at 1450 or 1950 nm is collected after a small radial divergence in diffuse reflectance mode. Light that is less absorbed, such as light near water absorbance minima at 1300, 1600, or 2250 nm, is collected at greater radial distances and is referred to as either transflected light or diffusely reflected light. Light collected after bouncing off of the outermost surface of skin is referred to as specularly reflected light.
Calibration
Optical based glucose concentration analyzers require calibration. This is true for all types of glucose concentration analyzers such as traditional invasive, alternative invasive, noninvasive, and implantable analyzers. A fundamental feature of noninvasive glucose analyzers is that they are secondary in nature, that is, they do not measure blood glucose concentrations directly. Therefore, a primary method is required to calibrate these devices to measure blood glucose concentrations properly. Many methods of calibration exist.
One noninvasive technology, near-infrared spectroscopy, requires that a mathematical relationship between an in-vivo near-infrared spectrum and the actual blood glucose concentration is developed. This relationship is achieved through the collection of in-vivo near-infrared measurements with corresponding blood glucose concentrations that have been obtained directly through the use of measurement tools like a traditional invasive or alternative invasive reference device.
For spectrophotometric based analyzers, there are several univariate and multivariate methods that are used to develop the mathematical relationship between the measured signal and the actual blood glucose concentration. However, the basic equation being solved is known as the Beer-Lambert Law. This law states that the strength of an absorbance/reflectance measurement is proportional to the concentration of the analyte which is being measured, as in equation 1,A=εbC  (1)where A is the absorbance/reflectance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance that the light travels, and C is the concentration of the molecule of interest.
Chemometric calibration techniques extract a glucose or glucose-related signal from acquired spectra through various methods of signal processing and calibration including one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements known as the calibration set and an associated set of reference blood glucose concentrations based upon an analysis of capillary blood or venous blood. Common multivariate approaches, requiring an exemplary reference glucose concentration for each sample spectrum in a calibration, include partial least squares (PLS) and principal component regression (PCR).
There are a number of reports of noninvasive glucose technologies. Some of these relate to general instrumentation configurations required for noninvasive glucose concentration estimation while others refer to sampling technologies. Those related to the present invention are briefly reviewed here:
General Instrumentation
R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determination of analyte concentration in body of mammals, U.S. Pat. No. 5,379,764 (Jan. 10, 1995) describe a noninvasive glucose concentration estimation analyzer that uses data pretreatment in conjunction with a multivariate analysis to determine blood glucose concentrations.
P. Rolfe, Investigating substances in a patient's bloodstream, UK patent application Ser. No. 2,033,575 (Aug. 24, 1979) describes an apparatus for directing light into the body, detecting attenuated backscattered light, and using the collected signal to determine glucose concentrations in or near the bloodstream.
C. Dahne, D. Gross, Spectrophotometric method and apparatus for the non-invasive, U.S. Pat. No. 4,655,225 (Apr. 7, 1987) describe a method and apparatus for directing light into a patient's body, collecting transmitted or backscattered light, and determining glucose concentrations from selected near-infrared wavelength bands. Wavelengths include 1560 to 1590, 1750 to 1780, 2085 to 2115, and 2255 to 2285 nm with at least one additional reference signal from 1000 to 2700 nm.
M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids, U.S. Pat. No. 4,975,581 (Dec. 4, 1990) describe a method and apparatus for measuring a concentration of a biological analyte such as glucose using infrared spectroscopy in conjunction with a multivariate model. The multivariate model is constructed from a plurality of known biological fluid samples.
J. Hall, T. Cadell, Method and device for measuring concentration levels of blood constituents non-invasively, U.S. Pat. No. 5,361,758 (Nov. 8, 1994) describe a noninvasive device and method for determining analyte concentrations within a living subject using polychromatic light, a wavelength separation device, and an array detector. The apparatus uses a receptor shaped to accept a fingertip with means for blocking extraneous light.
S. Malin, G Khalil, Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy, U.S. Pat. No. 6,040,578 (Mar. 21, 2000) describe a method and apparatus for estimation of an organic blood analyte using multi-spectral analysis in the near-infrared. A plurality of distinct nonoverlapping regions of wavelengths are incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques.
Specular Reflectance
R. Messerschmidt, D. Sting, Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum, U.S. Pat. No. 4,661,706 (Apr. 28, 1987) describe a reduction of specular reflectance by a mechanical device. A blade-like device skims the specular light before it impinges on the detector. A disadvantage of this system is that it does not efficiently collect diffusely reflected light and the alignment is problematic.
R. Messerschmidt, M. Robinson, Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,636,633 (Jun. 10, 1997) describe a specular control device for diffuse reflectance spectroscopy using a group of reflecting and open sections.
R. Messerschmidt, M. Robinson, Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,935,062 (Aug. 10, 1999) and R. Messerschmidt, M.
Robinson, Diffuse reflectance monitoring apparatus, U.S. Pat. No. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that discriminates between diffusely reflected light that is reflected from selected depths. This control device additionally acts as a blocker to prevent specularly reflected light from reaching the detector.
Malin, supra describes the use of specularly reflected light in regions of high water absorbance such as 1450 and 1900 nm to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe a mechanical device for applying sufficient and reproducible contact of the apparatus to the sampling medium to minimize specular reflectance. Further, the apparatus allows for reproducible applied pressure to the sampling site and reproducible temperature at the sampling site.
Temperature
K. Hazen, Glucose Determination in Biological Matrices Using Near-Infrared Spectroscopy, doctoral dissertation, University of Iowa (1995) describes the adverse effect of temperature on near-infrared based glucose concentration estimations. Physiological constituents have near-infrared absorbance spectra that are sensitive, in terms of magnitude and location, to localized temperature and the sensitivity impacts noninvasive glucose concentration estimation.
Coupling Fluid
A number of sources describe coupling fluids with important sampling parameters.
Index of refraction matching between the sampling apparatus and sampled medium is well known. Glycerol is a common index matching fluid for optics to skin.
R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,655,530 (Aug. 12, 1997), and R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,823,951 (Oct. 20, 1998) describe an index-matching medium for use between a sensor probe and the skin surface. The index-matching medium is a composition containing perfluorocarbons and chlorofluorocarbons.
M. Robinson, R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 6,152,876 (Nov. 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001) describe an index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis. The index-matching medium is preferably a composition containing chlorofluorocarbons with optional added perfluorocarbons.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guide placement guide, U.S. Pat. No. 6,415,167 (Jul. 2, 2002) describe a coupling fluid of one or more perfluoro compounds where a quantity of the coupling fluid is placed at an interface of the optical probe and measurement site. Perfluoro compounds do not have the toxicity associated with chlorofluorocarbons.
Positioning
T. Blank, supra describes the use of a guide in conjunction with a noninvasive glucose concentration analyzer in order to increase precision of the location of the sampled tissue site resulting in increased accuracy and precision in noninvasive glucose concentration estimations.
J. Griffith, P. Cooper, T. Barker, Method and apparatus for non-invasive blood glucose sensing, U.S. Pat. No. 6,088,605 (Jul. 11, 2000) describe an analyzer with a patient forearm interface in which the forearm of the patient is moved in an incremental manner along the longitudinal axis of the patient's forearm. Spectra collected at incremental distances are averaged to take into account variations in the biological components of the skin. Between measurements rollers are used to raise the arm, move the arm relative to the apparatus and lower the arm by disengaging a solenoid causing the skin lifting mechanism to lower the arm into a new contact with the sensor head. The Griffith teachings do not suggest the use of a controlled pressure between the forearm sampling site and the sampling head. In addition, spectra are not collected during a period of relative motion between the sample and the analyzer.
Pressure
E. Chan, B. Sorg, D. Protsenko, M. O'Neil, M. Motamedi, A. Welch, Effects of compression on soft tissue optical properties, IEEE Journal of Selected Topics in Quantum Electronics, Vol. 2, No. 4, pp. 943-950 (1996) describe the effect of pressure on absorption and reduced scattering coefficients from 400 to 1800 nm. Most specimens show an increase in the scattering coefficient with compression.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe in a first embodiment a noninvasive glucose concentration estimation apparatus for either varying the pressure applied to a sample site or maintaining a constant pressure on a sample site in a controlled and reproducible manner by moving a sample probe along the z-axis perpendicular to the sample site surface. In an additional described embodiment, the arm sample site platform is moved along the z-axis that is perpendicular to the plane defined by the sample surface by raising or lowering the sample holder platform relative to the analyzer probe tip. The '012 patent further teaches proper contact to be the moment specularly reflected light is about zero at the water bands at 1950 and 2500 nm.
M. Makarewicz, M. Mattu, T. Blank, G. Acosta, E. Handy, W. Hay, T. Stippick, B. Richie, Method and apparatus for minimizing spectral interference due to within and between sample variations during in-situ spectral sampling of tissue, U.S. Pat. No. 6,839,584 (Jan. 4, 2005) describe a temperature and pressure controlled sample interface. The means of pressure control are a set of supports for the sample that control the natural position of the sample probe relative to the sample.
To date, no FDA device has been approved for use by an individual or a medical professional for noninvasive glucose concentration estimation. Further, current reported versions of noninvasive glucose concentration analyzers do not consistently yield accurate estimations of glucose concentrations in patient trials. To be considered successful, the accuracy of estimated glucose concentrations needs to be better than 15 percent as compared to a blood analysis on greater than 90 percent of trial population. A key source of error in the glucose concentration estimation is related to the probe design and patient interface, as opposed to the spectrograph unit or algorithm design. A key parameter to control is the applied force, displacement, or pressure applied by the sample probe to the interrogated tissue volume or sample site. A force and/or displacement controlled sample interface is beneficial in generating reproducible sample spectra used in conjunction with a noninvasive analyzer and algorithm to create acceptable reproducibility and acceptable glucose concentration estimations.
Clearly, a need exists to control the load applied by the sample probe to the measurement site as a function of time.